Metal-free Cross-dehydrogenative Coupling Research Articles

Metal-free photoinduced C(sp3)–H/C(sp3)–H cross-coupling to access α‑tertiary amino acid derivatives

The cross-dehydrogenative coupling (CDC) reaction is the most direct and efficient method for constructing α-tertiary amino acids (ATAAs), which avoids the pre-activation of C(sp3)-H substrates. However, the use of transition metals and harsh reaction conditions are still significant challenges for these reactions that urgently require solutions. This paper presents a mild, metal-free CDC reaction for the construction of ATAAs, which is compatible with various benzyl C-H substrates, functionalized C-H substrates, and alkyl substrates, with good regioselectivity. Notably, our method exhibits excellent functional group tolerance and late-stage applicability. According to mechanistic studies, the one-step synthesized and bench-stable N-alkoxyphtalimide generates a highly electrophilic trifluoro ethoxy radical that serves as a key intermediate in the reaction process and acts as a hydrogen atom transfer reagent. Therefore, our metal-free and additive-free method offers a promising strategy for the synthesis of ATAAs under mild conditions.

Cyclic Hypervalent Iodine-Induced Oxidative Phenol and Aniline Couplings with Phenothiazines

C-H/N-H bond functionalization for direct intermolecular aryl C-N couplings is a useful synthetic process. In this study, we achieved metal-free cross-dehydrogenative coupling of phenols and anilines with phenothiazines using hypervalent iodine reagents. This method affords selective amination products under mild conditions. Electron-rich phenols and anilines could be employed, affording moderate-to-high yields of N-arylphenothiazines. Aniline amination proceeded efficiently at 20 °C, a previously unreported phenomenon.

Developments in Organocatalyzed C(Ar)- C(Ar) Bond formation Reactions Involving Single Electron Transfer Mechanism: An Overview

The formation of new bonds through C-C bond formation is of utmost importance in the synthesis of biologically privileged scaffolds and therapeutic drugs. In recent years, extensive efforts has been done to improve the intermolecular and intramolecular cross-coupling reaction in the simple, mild, efficient, economical, and eco-friendly manner via transition metal-free or organocatalytic direct C-H bond activation methodology. The traditional cross-coupling era continuously shifted to metal-free, organocatalytic, or metal-free cross-dehydrogenative coupling strategies to fast-track the reactions and diminishing the typical purification processes. Therefore, recent advances on the transition-metal-free, organocatalytic inter- and intra-molecular cross-coupling reactions have been introduced and discussed in the present article. In view of the reaction mechanism, organocatalytic cross-coupling reactions undergo through radical pathways, radical anionic intermediate which is completely different from traditional transition metal-catalyzed reactions. The exploration of transition metal-free organocatalyzed cross-couplings for direct C-H arylation of arenes has grown significantly, thereby, improving the formation of a wide range of aryl-aryl /arylheteroaryl/ heteroaryl-heteroaryl compounds. In the survey, transition metal-free/organocatalytic cross-coupling reactions showed a higher efficiency under simple and mild conditions than the comparative transition metal-catalyzed cross-coupling reactions. However, the higher regioselectivity and chemoselectivity are still far ahead in organocatalytic cross-coupling reactions due to their specific intrinsic mechanistic pathway. The tuning of many parameters such as oxidative states, ligands coordination, and counter anions, etc., which results in the specific direct C-H functionalization with flexible methodology are missing in the transition metal-free cross-coupling reactions. The highly systematic transition metal-catalyzed chemistry is still playing a dominant role over transition metal-free chemistry in organic synthesis. The organocatalyzed transition-metal-free conditions should be more efficient, chemoselective, and regioselective for further potential development and applications in organic synthesis. For the endless pursuit of sustainable chemistry and green chemistry, such transition-metal-free/organocatalytic reactions should be never ceased. Additional curious attention and interest have been developed so far, and chemists are showing their eagerness and talents to uncover the hidden treasure of green chemistry. In this review article, we highlighted the developments of various transition metal-free/organocatalytic C-H bond activation reactions which further encourages the advancement in the development of sustainable C-C coupling reactions and their further applications towards the synthesis of biologically privileged scaffolds and drug molecules.

Direct para-C–H heteroarylation of anilines with quinoxalinones by metal-free cross-dehydrogenative coupling under an aerobic atmosphere

This study demonstrates a metal-free cross-dehydrogenative coupling for direct para-C–H heteroarylation of anilines with quinoxalinones using air as the sole oxidant and H2O/DMSO as the solvent.

Diacetyl as a "traceless" visible light photosensitizer in metal-free cross-dehydrogenative coupling reactions.

Minisci alkylation is of prime importance for its applicability in functionalizing diverse heteroarenes, which are core structures in many bioactive compounds. In alkyl radical generation processes, precious metal catalysts, high temperatures and excessive oxidants are generally involved, which lead to sustainability and safety concerns. Herein we report a new strategy using diacetyl (2,3-butanedione) as an abundant, visible light-sensitive and "traceless" hydrogen atom abstractor to achieve metal-free cross-dehydrogenative Minisci alkylation under mild conditions. Mechanistic studies supported hydrogen atom transfer (HAT) between an activated C(sp3)-H substrate and diacetyl. Moreover, with the assistance of di-tert-butyl peroxide (DTBP), the scope of the reaction could be extended to strong aliphatic C-H bonds via diacetyl-mediated energy transfer. The robustness of this strategy was demonstrated by functionalizing complex molecules such as quinine, fasudil, nicotine, menthol and alanine derivatives.

Metal-free oxidative cross-dehydrogenative coupling of quinones with benzylic C(sp3)-H bonds.

A metal-free cross-dehydrogenative coupling of quinones with toluene derivatives has been established. A series of quinones were subjected to reaction with toluene derivatives in the presence of di-tertbutyl peroxide (DTBP) for direct synthesis of benzylquinones. The method exhibits good functional group tolerance, and desired products were obtained in moderate to good yields. Meanwhile, a radical pathway was proposed to describe the cross-dehydrogenative coupling of quinones with toluene derivatives.

Metal-Free Cross-Dehydrogenative Coupling (CDC): Molecular Iodine as a Versatile Catalyst/Reagent for CDC Reactions.

The development of ecofriendly methods for carbon-carbon (C-C) and carbon-heteroatom (C-Het) bond formation is of great significance in modern-day research. Metal-free cross-dehydrogenative coupling (CDC) has emerged as an important tool for organic and medicinal chemists as a means to form C-C and C-Het bonds, as it is atom economical and more efficient and greener than transition-metal catalyzed CDC reactions. Molecular iodine (I2 ) is recognized as an inexpensive, environmentally benign, and easy-to-handle catalyst or reagent to pursue CDCs under mild reaction conditions, with good regioselectivities and broad substrate compatibility. This review presents the recent developments of I2 -catalyzed C-C, C-N, C-O, and C-S/C-Se bond-forming reactions for the synthesis of various important organic molecules by cross-dehydrogenative coupling.

Transition Metal-Free Cross-Dehydrogenative Coupling Reaction of Coumarins with Acetonitrile or Acetone.

A transition metal-free cross-dehydrogenative coupling of coumarins with acetonitrile or acetone has been established. A series of coumarins were subjected to reaction with acetonitrile or acetone in the presence of tert-butyl benzoperoxoate and potassium fluoride for direct synthesis of 3-cyanomethyl (or acetomethyl) coumarins. The method exhibits good functional group tolerance, and desired products were obtained in moderate to good yields. Meanwhile, a radical pathway was proposed to describe the cross-dehydrogenative coupling of coumarins with acetonitrile.

Metal‐free cross‐dehydrogenative coupling approach for C‐H bond functionalization of 2‐phenyl pyridine derivatives in water

AbstractWe have developed a simple K2S2O8‐mediated C‐H bond functionalization of 2‐phenyl pyridines (C‐2 position) with ethers involving C(sp2)‐C(sp3) cross‐dehydrogenative coupling. The reaction does not require metal catalysts nor visible light and operates under mild conditions. Furthermore, the protocol is easily scalable and extendable to a wide range of pyridine derivatives.

Bromine-Mediated Cross-Dehydrogenative Coupling (CDC) Reactions

Abstract Significant advances in the development of CDC reactions have been made in recent years. However, metal-free CDC reaction remains comparatively under-developed. In view that a variety of readily available, cheap and environmentally friendly bromine reagents have been employed in bromination or oxidation in organic synthesis, we would like to summarize and discuss in this review examples of bromine-mediated CDC reactions, delineating significant and promising applications of these reagents in metal-free functionalization of C-H bonds.

Andrey P. Antonchick

Angewandte Chemie International EditionVolume 56, Issue 40 p. 12042-12042 Author ProfileFree Access Andrey P. Antonchick First published: 10 May 2017 https://doi.org/10.1002/anie.201704212AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract “The secret of being a successful scientist is patience. My favorite name reaction is the Belousov–Zhabotinsky reaction ...” This and more about Andrey P. Antonchick can be found on page 12042. Andrey P. Antonchick The author presented on this page has recently published his 25th article since 2006 in Angewandte Chemie: “General Enantioselective C−H Activation with Efficiently Tunable Cyclopentadienyl Ligands”: Z.-J. Jia, C. Merten, R. Gontla, C. G. Daniliuc, A. P. Antonchick, H. Waldmann, Angew. Chem. Int. Ed. 2017, 56, 2429; Angew. Chem. 2017, 129, 2469. Date of birth: September 14, 1976 Position: Group leader, Technische Universität Dortmund E-mail: andrey.antonchick@tu-dortmund.de Homepage: http://antonchick.de ORCID: 0000-0003-0435-9443 Education: 2000 Undergraduate degree, Belarusian State University, Minsk 2005 PhD supervised by Prof. Dr. Vladimir Khripach (Institute of Bioorganic Chemistry of the National Academy of Sciences of Belarus) and Dr. Bernd Schneider (Max Planck Institute for Chemical Ecology, Jena) 2005–2008 Postdoctoral fellow with Prof. Dr. Magnus Rueping, University of Frankfurt 2008–2011 Postdoctoral fellow with Prof. Dr. Herbert Waldmann, Max Planck Institute of Molecular Physiology, Dortmund Awards: 2012 Thieme Chemistry Journals Award; 2017 visiting professorship, Peoples’ Friendship University of Russia Research: Reaction methodology, asymmetric catalysis, chemical biology Hobbies: Skiing, soccer The secret of being a successful scientist is patience. My favorite name reaction is the Belousov–Zhabotinsky reaction. My science “heroes” are Sofia V. Kovalevskaya, Alexander Fleming, Christiaan N. Barnard, Paul Ehrlich, Giordano Bruno, and many more. If I had one year of paid leave I would do some experiments in the lab. If I could be a piece of lab equipment, I would be a magnetic stir bar. The principal aspects of my personality are honesty and fairness. My favorite bands are Depeche Mode, The Cure, and Portishead. When I was eighteen I wanted to be a chemist. The most significant historic event of the past 100 years was space flight. My first experiment was the synthesis of nitrogen triiodide. My biggest inspiration is nature. My favorite times of day are early morning and late evening. My favorite way to spend a holiday is skiing. My 5 top papers: References 1“[1+1+1] Cyclotrimerization for the Synthesis of Cyclopropanes”: S. Manna, A. P. Antonchick, Angew. Chem. Int. Ed. 2016, 55, 5290; Angew. Chem. 2016, 128, 5376. (A radical cascade reaction for the simple synthesis of small rings.) 2“Cascade Multicomponent Synthesis of Indoles, Pyrazoles, and Pyridazinones by Functionalization of Alkenes”: K. Matcha, A. P. Antonchick, Angew. Chem. Int. Ed. 2014, 53, 11960; Angew. Chem. 2014, 126, 12154. (A general approach to heterocycle synthesis.) 3“Organocatalytic Oxidative Annulation of Benzamide Derivatives with Alkynes”: S. Manna, A. P. Antonchick, Angew. Chem. Int. Ed. 2014, 53, 7324; Angew. Chem. 2014, 126, 7452. (We demonstrated how transition-metal catalysts can be omitted in C−H bond functionalization.) 4“Metal-Free Cross-Dehydrogenative Coupling of Heterocycles with Aldehydes”: K. Matcha, A. P. Antonchick, Angew. Chem. Int. Ed. 2013, 52, 2082; Angew. Chem. 2013, 125, 2136. (One of the most practical reactions that was developed in my group.) 5“Palladium-Catalyzed Double C−H Activation Directed by Sulfoxides in the Synthesis of Dibenzothiophenes”: R. Samanta, A. P. Antonchick, Angew. Chem. Int. Ed. 2011, 50, 5217; Angew. Chem. 2011, 123, 5323. (Your first independent publication is like your first love!) Volume56, Issue40September 25, 2017Pages 12042-12042 ReferencesRelatedInformation

Iodine-Catalyzed C-N Bond Formation: Synthesis of 3-Aminoquinoxalinones under Ambient Conditions.

A metal-free cross-dehydrogenative coupling between quinoxalinones (sp2 C-H) and amines (N-H) in the presence of catalytic iodine is reported. The reaction yields 3-aminoquinoxalinones in moderate to high yields under ambient conditions in dioxane as solvent and aqueous tert-butyl hydroperoxide (TBHP) as the terminal oxidant. The reaction is highly versatile and exhibits good functional group tolerance with a range of primary and secondary amines. It provides a practical access to pharmaceutically active 3-aminoquinoxalinone derivatives. Preliminary mechanistic studies reveal in situ iodination of the amine as the putative mode of activation.

CDC Reaction and Subsequent Cyclization for the Synthesis of 2-Hydroxy-3-alkyl-1,4-naphthoquinones and Pyranonaphthoquinones.

The metal-free cross-dehydrogenative coupling (CDC) reaction and subsequent cyclization of 2-hydroxy-1,4-naphthoquinone (lawsone) and 1,3-diarylpropene promoted by DDQ has been developed. 2-Hydroxy-3-alkyl-1,4-naphthoquinones and pyranonaphthoquinones with potential pharmaceutical applications are obtained in moderate to good yields. The reaction is also compatible for 4-hydroxycoumarins.

Metal-free Cross-Dehydrogenative Coupling of HN-azoles with α-C(sp3)-H Amides via C-H Activation and Its Mechanistic and Application Studies.

A metal-free one step coupling reaction between various N-azole rings and diverse α-C(sp3)-H containing amides has been developed under oxidative reaction conditions. Commercially available tetrabutyl ammonium iodide (TBAI) in the presence of terbutylhydroperoxide (TBHP), under neat reaction condition, efficiently catalyzed the coupling. Various azole types, such as 1H-benzotriazoles, 1H-1,2,3-triazoles, 1H-1,2,4-triazoles, 1H-tetrazoles, 1H-pyrazoles, and 1H-benzimidazoles, and α-C(sp3)-H containing amides, such as N,N-dimethylacetamide, N,N-dimethylbenzamide, N-methylacetamide, N,N-diethylacetamide, N-methylpyrrolidine, and pyrrolidine-2-one, were successfully employed for the coupling. A series of designed and controlled experiments were also performed in order to study the involvement of the different intermediates. Based on the evidence, a plausible mechanism is also proposed. These novel, simple, rapid, attractive, and straightforward transformations open the way of the construction of novel highly functionalized N-azoles via direct covalent N-H bond transformations onto N-C bonds. This approach allows to the synthesis of complex molecules requiring number of steps using classical synthetic ways. In addition, the range of α-C(sp3)-H containing amide substrates is virtually unlimited highlighting the potential value of this simple system for the construction of complex heterocyclic molecules, such as fused azoles derivatives.

ChemInform Abstract: Regioselective Transition Metal‐Free Acylation of Coumarins via Cross‐Dehydrogenative Coupling Reaction of Coumarins and Aldehydes.

Abstract A transition metal-free cross-dehydrogenative coupling reaction is described for the preparation of 3-acylcoumarins. Heating a mixture of a coumarin, an aldehyde, and the K 2 S 2 O 8 /Aliquat 336 system in chlorobenzene at 100 °C for 8 h regioselectively afforded the corresponding 3-acylcoumarin derivatives in good to excellent yields.

A Metal-Free Cross-Dehydrogenative Coupling Reaction of Amides to Access N-Alkylazoles

An iodine-catalyzed cross-dehydrogenative coupling reaction of N-alkyl amides and azoles is reported. The catalytic system provides an efficient method for introducing amides onto azoles, especially onto benzotriazoles.

Regioselective transition metal-free acylation of coumarins via cross-dehydrogenative coupling reaction of coumarins and aldehydes

A transition metal-free cross-dehydrogenative coupling reaction is described for the preparation of 3-acylcoumarins. Heating a mixture of a coumarin, an aldehyde, and the K2S2O8/Aliquat 336 system in chlorobenzene at 100°C for 8h regioselectively afforded the corresponding 3-acylcoumarin derivatives in good to excellent yields.

Metal-free cross-dehydrogenative coupling of aryl aldehydes to give symmetrical carboxylic anhydrides promoted by the TBHP/nBu4PBr system

A novel, efficient, and metal-free dual C–O bond formation reaction for the synthesis of carboxylic anhydrides from aryl aldehydes via cross-dehydrogenative coupling is described. Heating a mixture of aromatic aldehydes and an aqueous solution of tert-butyl hydroperoxide as oxidant in the presence of catalytic nBu4PBr in chlorobenzene at 80°C for 3h afforded the corresponding carboxylic anhydrides in good to excellent yields.

Transition metal-free cross-dehydrogenative coupling acylation of coumarins by the K2S2O8/Aliquat 336 catalytic system: a versatile strategy towards 4-aroylcoumarin derivatives

A new and efficient transition metal-free oxidative cross-dehydrogenative coupling (CDC) reaction is described for the preparation of 4-aroylcoumarin derivatives.

Cross-dehydrogenative coupling of azoles with α-C(sp3)-H of ethers and thioethers under metal-free conditions: functionalization of H-N azoles via C-H activation.

A metal-free cross-dehydrogenative coupling method for the synthesis of N-substituted azoles has been developed. The TBAI/TBHP system catalyzed the coupling of azoles with ethers and thioethers via α-C(sp(3))-H activation. Under the optimized conditions, a diverse range of un/substituted azoles such as 1H-benzimidazole, 9H-purine, 1H-benzotriazole, 1H-1,2,3-triazole, 1H-1,2,4-triazole, and 1H-pyrazole were successfully employed for coupling with various ethers and thioethers such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, diethyl ether, tetrahydrothiophene, and 1,3-dithiolane.